While neurodegenerative diseases and cancer are traditionally studied by investigators in completely separate fields, it has become increasingly clear that the genetics associated with risk of developing either type of disease often overlap. Hereditary mutations to leucine-rich repeat kinase 2 (LRRK2) are a particularly good example of this phenomenon, as the activating G2019S mutation to LRRK2 significantly increases the risk of developing Parkinson's Disease and a spectrum of solid tumors including renal cancer. While a significant amount of effort has been invested in the neurodegenerative aspects of LRRK2 function, less attention has been given to the oncogenic effect of LRRK2 hyperactivation in epithelial tissues. In parallel to the discovery of hereditary cancer risk associated with LRRK2 point mutations, previous studies by this this investigator identified genomic amplification of LRRK2 in the etiology of papillary renal cell carcinoma. This initial study indicated a cooperative mechanism of cellular transformation involving overexpression of LRRK2 and the receptor tyrosine kinase MET, though the cellular mechanisms underlying this association are unclear. Ongoing research suggests that LRRK2 is a critical regulator of endosomal trafficking in various epithelial compartments, including the proximal renal tubule epithelia from which papillary renal cancers arise. This study hypothesizes that increased LRRK2 activity-due to its genomic amplification or mutation-modifies trafficking of auto-activated MET receptors, resulting in increased endosomal retention and prolonged activation. This mechanism of ligand-independent MET activation amplifies signaling to endosomal effectors including the JAK/STAT and TORC1 signaling pathways, which are otherwise not prominently activated by MET. This hypothesis will be tested in the specific context of renal cell carcinoma, where LRRK2 is commonly overexpressed along with wild-type MET receptors. The approach will primarily involve cell biological and biochemical analyses of transformed renal cell carcinoma lines and normal immortalized proximal tubule epithelial cells. These complementary models address the effects of removing LRRK2 from transformed cells in which LRRK2 and MET are overexpressed/hyperactive, and to increase expression of LRRK2 and MET in normal cells where both proteins are expressed at low basal levels. This project provides an excellent basis for training undergraduate students in the principles of cellular transformation, as well as the experimental tools required to answer mechanistic questions about these principles in the laboratory.